A unique intracellular tyrosine in neuroligin-1 regulates AMPA receptor recruitment during synapse differentiation and potentiation

Mathieu Letellier, Zsófia Szíber, Ingrid Chamma, Camille Saphy, Ioanna Papasideri, Béatrice Tessier, Matthieu Sainlos, Katalin Czöndör, Olivier Thoumine
Nat Commun. 2018-09-28; 9(1):
DOI: 10.1038/s41467-018-06220-2

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To better understand the molecular mechanisms by which early neuronal connections
mature into synapses, we examined the impact of neuroligin-1 (Nlg1)
phosphorylation on synapse differentiation, focusing on a unique intracellular
tyrosine (Y782), which differentially regulates Nlg1 binding to PSD-95 and
gephyrin. By expressing Nlg1 point mutants (Y782A/F) in hippocampal neurons, we
show using imaging and electrophysiology that Y782 modulates the recruitment of
functional AMPA receptors (AMPARs). Nlg1-Y782F impaired both dendritic spine
formation and AMPAR diffusional trapping, but not NMDA receptor recruitment,
revealing the assembly of silent synapses. Furthermore, replacing endogenous Nlg1
with either Nlg1-Y782A or -Y782F in CA1 hippocampal neurons impaired long-term
potentiation (LTP), demonstrating a critical role of AMPAR synaptic retention.
Screening of tyrosine kinases combined with pharmacological inhibitors point to
Trk family members as major regulators of endogenous Nlg1 phosphorylation and
synaptogenic function. Thus, Nlg1 tyrosine phosphorylation signaling is a
critical event in excitatory synapse differentiation and LTP.

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